To understand what was driving the beneficial effect of young serum, Sahu and colleagues cataloged the EV cargo. They found that EVs display an age-associated decrease in mRNA levels of Klotho. This longevity protein has been positively associated with maintaining mitochondrial bioenergetics and skeletal muscle health. Notably, the researchers found that the impact of young EVs on muscle progenitor cell bioenergetics and skeletal muscle regeneration depended on the presence of Klotho mRNA.
To show that the beneficial effect of young EVs on muscle regeneration is dependent on Klotho transcript levels, Sahu and colleagues EVs isolated from young mice that either had half of the genetic material encoding Klotho deleted or were genetically unaltered were injected into old mice, which contained significantly reduced levels of Klotho mRNA. Compared to those that received EVs from mice with the complete set of genetic material, aged animals receiving EVs from young mice missing half the genetic material encoding Klotho displayed a significant decrease in large myofibers, increased muscle fiber scarring (fibrosis), and impaired force recovery.